Longo also discussed a promising new approach to protecting healthy cells from the harmful side effects of chemotherapy through fasting.
Starved healthy cells go into survival mode, Longo explained, characterized by extreme resistance to stresses. In essence, these cells are waiting out the lean period, much like hibernating animals. But cancerous tumors respond differently to starvation; they do not stop growing, nor do they hibernate because their genetic pathways are stuck in an “on” mode.
Longo realized that the starvation response might differentiate healthy cells from cancer cells by their increased stress resistance and that healthy cells might withstand much more chemotherapy than cancer cells.

Not a Magic Bullet, But a Magic Shield

USC biologists discover a way to protect healthy cells against chemotherapy.

Fasting for two days protects healthy cells against chemotherapy, according to a study appearing online the week of March 31 in PNAS Early Edition.
Mice given a high dose of chemotherapy after fasting continued to thrive. The same dose killed half the normally fed mice and caused lasting weight and energy loss in the survivors.
The chemotherapy worked as intended on cancer, extending the lifespan of mice injected with aggressive human tumors, reported a group led by Valter Longo of the USC Davis School of Gerontology and USC College.
Test tube experiments with human cells confirmed the differential resistance of normal and cancer cells to chemotherapy after a short period of starvation.
Making chemotherapy more selective has been a top cancer research goal for decades. Oncologists could control cancers much better, and even cure some, if chemotherapy was not so toxic to the rest of the body.
Experts described the study as one of a kind.
“This is a very important paper. It defines a novel concept in cancer biology,” said cancer researcher Pinchas Cohen, professor and chief of pediatric endocrinology at UCLA.
“In theory, it opens up new treatment approaches that will allow higher doses of chemotherapy. It’s a direction that’s worth pursuing in clinical trials in humans.”
Felipe Sierra, director of the Biology of Aging Program at the National Institute on Aging, said, “This is not just one more anti-cancer treatment that attacks the cancer cells. To me, that’s an important conceptual difference.”
Sierra was referring to decades of efforts by thousands of researchers working on “targeted delivery” of drugs to cancer cells. Study leader Longo focused instead on protecting all the other cells.
Sierra added that progress in cancer care has made patients more resilient and able to tolerate fasting, should clinical trials confirm its usefulness.“We have passed the stage where patients arrive at the clinic in an emaciated state. Not eating for two days is not the end of the world,” Sierra said.
“This could have applicability in maybe a majority of patients,” said David Quinn, a practicing oncologist and medical director of USC Norris Hospital and Clinics. He predicted that many oncology groups would be eager to test the Longo group’s findings and advised patients to look for a clinical trial near home.
Longo, an anti-aging researcher who holds joint appointments in gerontology and biological sciences at USC, said that the idea of protecting healthy cells from chemotherapy may have seemed impractical to cancer researchers because the body has many different cells that respond differently to many drugs.
“It was almost like an idea that was not even worth pursuing,” Longo said. “In fact it had to come from the anti-aging field because that’s what we focus on: protecting all cells at once.”
According to Cohen, “What really was missing was a perspective of someone from the aging field to give this field a boost.”
The idea for the study came from the Longo group’s previous research on aging in cellular systems, primarily lowly baker’s yeast.
About five years ago, Longo was thinking about the genetic pathways involved both in the starvation response and in mammalian tumors. When the pathways are silenced, starved cells go into what Longo calls a maintenance mode characterized by extreme resistance to stresses. In essence, the cells are waiting out the lean period, much like hibernating animals.
But tumors by definition disobey orders to stop growing because the same genetic pathways are stuck in an “on” mode.
That could mean, Longo realized, that the starvation response might differentiate normal and cancer cells by their stress resistance and that healthy cells might withstand much more chemotherapy than cancer cells.
The shield for healthy cells does not need to be perfect, Longo said. What matters is the difference in stress resistance between healthy and cancerous cells.
During the study, conducted both at USC and in the laboratory of Lizzia Raffaghello at Gaslini Children’s Hospital in Genoa, Italy, the researchers found that current chemotherapy drugs kill as many healthy mammalian cells as cancer cells.
“(But) we reached a two to five-fold difference between normal and cancer cells, including human cells in culture. More importantly, we consistently showed that mice were highly protected while cancer cells remained sensitive,” Longo said.
If healthy human cells were just twice as resistant as cancer cells, oncologists could increase the dose or frequency of chemotherapy.
“We were able to reach a 1,000-fold differential resistance using a tumor model in baker’s yeast. If we get to just a 10–20 fold differential toxicity with human metastatic cancers, all of a sudden it’s a completely different game against cancer,” Longo said.
“Now we need to spend a lot of time talking to clinical oncologists to decide how to best proceed in the human studies.”
Edith Gralla, a research professor of chemistry at UCLA, said, “It is the sort of opposite of the magic bullet. It’s the magic shield.”
Funding from the study came from the National Institute on Aging (part of the National Institutes on Health), the USC/Norris Cancer Center and the Associazione Italiana per la Lotta al Neuroblastoma.
USC graduate student Changhan Lee and Gaslini’s Raffaghello performed key experiments. The other authors were Fernando Safdie, Min Wei and Federica Madia of USC and Giovanna Bianchi of Gaslini.
Longo has been studying aging at the cellular level for 15 years and has published in the nation’s leading scientific journals. He is the Albert L. and Madelyne G. Hanson Family Trust Associate Professor at the USC Davis School with joint appointments as associate professor of biological sciences at USC College and in the Norris Cancer Center.For Clinicians and Patients
Fasting before chemotherapy has unknown risks and benefits for humans, Longo cautioned. Only clinical trials can establish the effectiveness and safety of fasting before chemotherapy.
“Don’t try and do this at home. We need to do the studies,” said Quinn, the USC Norris oncologist.

History of dietary/caloric restriction theory: restriction by 30% thought to reduce incidence and growth amongst all cancers.

Current research found disparities in response

divided cancers into responsive/unresponsive

Resistant cancers, when cell analyzed didn't care about insulin growth factors. Responsive cancers followed insulin levels tightly which implicated PI3 kinase pathway, one of the major systems of response to insulin levels.
Looked at the two types of cells and found Pi3 kinase pathways differed, resistant cells had mutated PI3 kinase pathways. Manipulation of pathway could induce resistance or responsiveness showing causation and identified PI3K as pivotal.
Mimetics (metformin?) of caloric restriction could prove helpful. However findings suggest need to identify which tumors will respond.

Despite prevalent thinking that restriction worked on all tumors, closer look at data from the 30's actually does show disparities.

Identification of main pathway/response determination is biggest finding. Simplifies what was thought to be a complex process. Insulin levels drop when you calorically restrict. But here's a (mutated) pathway that lets the cells think there's always insulin.

If caloric restriction important the reverse is implicated. Obesity may be biggest driver of increased cancer. Need to find out role of mutated pathway in obese patients.

Fasting can protect cells from stress and damage, such as oxidation or radiation, and has been found to protect healthy cells from chemotherapy. But can the practice also help fight cancer?
There is now evidence to support this idea, from research on cancer models of yeast and tumor-ridden mice, published today (February 8) in Science Translational Medicine. Starved organisms survived longer when treated with chemotherapy than those on a normal diet, and healthy cells were less likely to sustain damage.
“This ability to think about adding fasting in combination with chemotherapy is obviously exciting, and it definitely adds something to the arsenal of what we can do,” said Trudy Oliver, who researches cancer resistance at the University of Utah but was not involved in the study.
Chemotherapy works by attacking rapidly dividing cells, a hallmark of cancer. Previous studies suggested that fasting before treatment could help protect healthy cells by slowing their growth even further. But one question loomed in researchers’ minds: “What happens to the cancer cells?” said study co-author Valter Longo, who studies the molecular mechanisms of aging at the University of Southern California. If fasting slowed down cancer cell growth enough to reduce the effectiveness of chemotherapy, “this would be a problem.”Initial results in cancer-mimic yeast and cancerous mammalian cell lines provided Longo with evidence that starvation slows cancer growth and also enhances healthy cell survival when faced with chemotherapy. These results encouraged Longo to move into mouse models. “If it doesn’t change from yeast to mammalian cells, we figured that it is something so conserved and fundamental it’s going to apply to humans too,” he said.
Longo’s team studied a variety of mouse models. Mice were injected with both human and mouse cancers, including breast cancer, melanoma, and the nervous system cancer neuroblastoma, among others. The researchers also tested several types of chemotherapy drugs. And each experimental combination was subjected to three treatments: just fasting, by being given only water for 48–60 hours prior to treatment, just chemotherapy, or fasting and chemo together.Results varied by cancer type and treatment, but overall the combination of fasting and chemotherapy reduced cancer growth significantly, and starved mice survived far longer than their non-starved counterparts. For example, melanoma metastasis was found in 40 percent of mice given just chemotherapy, 20 percent under starving conditions alone, and 10 percent of mice that underwent chemotherapy and fasting.“The surprising part was that, for several cancers including breast cancer, fasting cycles alone were as good as chemotherapy,” said Longo. “We expected some delay but not an equivalent effect.”

Quote:

There are already three clinical trials— one of which is at the University of Southern California—underway studying the combination of fasting and chemotherapy in human patients.Longo suspects that the human equivalent of 48–60 hours of mouse fasting is about five days, based on glucose and growth factor concentrations. Five days is a long time, noted Oliver, and fasting “may be rough for cancer patients who are already going through a lot.” But uncovering the mechanism could lead to better solution, she added.“It might be that people don’t need to starve to do the same thing, if they can take a new drug with chemotherapy that mimics starvation but is not as painful as starvation,” Oliver said. “That underscores the importance of finding the mechanism.”

This is one of several similar findings. An editorial in the Journal of Clinical Oncology by University of Chicago researchers that ruffled some industry feathers by arguing that taking Tykerb with fatty meals (the label says not to) is synergistic, greatly improved absorption and could lead to reduced doses (by 60%) which means less cost for the $2,900-a-month price tag, and reduced side effects, particularly diarrhea.

A company-sponsored study showed that Tykerb blood levels increased by 167% when taken with a low-fat meal, compared with taking the drug on an empty stomach -- and by 325% after a high-fat meal. Researchers, Drs. Mark Ratain and Ezra Cohen, argue that these kinds of food-drug interactions should be explored to lower drug costs.

And if taken with grapefruit juice, the potential cost savings could be about 80%, since Tykerb interacts with CYP3A4. Powerful compounds in the grapefruit called furanocoumarins obliterate the CYP3A4 enzyme in the intestines and liver. The result is that more of the drug gets into the bloodstream.

Individuals have different levels of CYP3A4 that breaks down drugs before they even have the chance to get into the bloodstream. Patients with very active CYP3A4 get lower amounts of drugs into their systems than those with low levels of the enzyme. Some patients may have naturally low levels of the CYP3A4 enzyme and thus wouldn't need it,

Certain drugs have a hard time reaching optimal blood levels at prescribed doses. Some doctors are interested in intentionally boosting the effects with grapefruit.

In addition to Tykberb, Zytiga (abiraterone) is also better absorbed with food, though (it too) the label says empty stomach. Cell function analysis has been able to reverse Zytiga resistance by having patients take it with a fatty meal.

Actually, the oral meds with food/fats seems more of an absorption/net dosage issue as opposed to the idea of fasting allowing normal cells to pull out of the target zone of typical chemo. But it is interesting if Tykerb absorption could be increased/maintained with lower dose comibined with certain foods. Suggests the dreaded Tykerrhea™ is more due to the pill base irritating the digestive tract as opposed to the circulating drug.

The rainbow beauty of fasting if it works in humans, is that it is under patient control. It is not some drug we have to wait 15 years for approval that is usually limited anyway. Im praying it works. I didnt read the articles carefullyyet or really research them. Could fasting before chemo decrease hair loss? That would be fantastic.

I fasted with my very first chemos back in 2009, after contacting Mr Longo at USC. My very first scans showed the cancer had cleared from my lungs and bones, some healed completely. Needless to say, I am still here and now trying the ketogenic diet, after reading "Cancer as a Metabolic Disease" and more suited to the lay person "Tripping Over the Truth."

__________________
Breastfeeding when diagnosed with Her2+ May 2008
Oct 2008 Double mastectomy 22/28 lymph nodes positive
Decline chemotherapy (decision I regret)
Nov 2009 Mets to lungs and bones.
Dec 2009 Start Taxotere and Herceptin, T1, T3 heal completely and lungs are clear, T2 and first rib have lytic lesions. First rib becomes sclerotic. Considered stable.
May 2011, Onc calls progression and I cross over from comparison arm of clinical trial to TDM-1
Brain scan in Sept 2011 showed small tumor in right cerebellum, did Novalis radiation.

Feb 2013 < 1cm tumor in left frontal lobe. Did Novalis in March and latest scan shows no sign of brain metastasis.
Aug 2013 did 36th round of TDM-1 Due to TDM-1 side effects, shortness of breath, and difficulty getting my balance when getting out of bed, agreed with my oncologist to stop TDM-1.
Took a six week break, bone scan showed small uptake on left first rib. CT showed hypodensities in liver (too small to biopsy) and small nodule in lungs (mediastinal).
Started Navelbine weekly. Did one round with Herceptin.
Skipped next 2 rounds, due to neutropenia. Next chemo 7th Nov - have had 3 Neupogen shots, so WBC should look better... Did not tolerate Navelbine well.
December 2013 scans show no sign of active cancer.
March 2014 - currently only on Herceptin - brain MRI clear, PET/CT two nodules in right lung show uptake
May 2014 - stop Herceptin.
Sept 22, 2014 Brain MRI clear :) PET/CT Progression in lungs.
Sept 2014, Xeloda, Tykerb and Herceptin.
Nov 2014 - Decide to take a break from all treatment.
May 2015 - Brain met radiated with Novalis
July 2015 - Have progression in right lung.
Sept 2015 - Perjeta and Herceptin alone after a 9 month break from all treatment.
Nov 2015 - Thoracentesis 1500ml removed from right lung.
Dec 2015 - Two tiny 1mm brain mets radiated in right cerebellum.
Feb 2016 - Thoracentesis 2200ml drained from right lung
Feb 2016 - Stopped Perjeta and Herceptin and started back on Kadcyla as I had no previous progression on it. After 1 cycle of Kadcyla markers begin to drop. On second cycle add Keytruda.
March 2016 - Thoracentesis 1650ml drained from right lung.
April 2016 – Thoracentesis 1500 ml drained from right lung.
June 2016 – CT scan shows progression in right lung, as well as moderate pleural effusion requiring Thoracentesis.
June 2016 – Decide to stop Keytruda, and will do chemosensitivity test through Rational Therapeutics. Plan to continue on Kadcyla for next two cycles.
July 2016 - Start weekly Abraxane with Herceptin. WBRT with hippocampal sparing, Taking Namenda. 15 sessions over 3 weeks.
Aug - Dec 2016 - 2 infusions of Navelbine, very hard on my body and still dealing with anasarca (generalized edema) 1 infusion of Havalen
My doctor wants to put me on hospice.
Dec 23rd 2016 - I am granted compassionate use of Neratanib.
May 31st 2017 - still on Neratinib, feeling good.

I agree about the weight loss, I am doing a calorie-reduced ketogenic diet. Thanks for sharing. I find that I can only do intermittent fasting, about 24-28 hours at most. Then I have to eat something so I eat salmon or eggs, or cheese.

waterdreamer, were you able to fast during your last rads for your brain mets? I'm in the midst of getting fractionated SRS to 2 of my lesions. 2 down. 3 to go.

I have never thought about fasting through brain rads, because I have always had such a good response. But after reading Tripping Over the Truth, and Cancer as a Metabolic Disease, it is something I would do in the future. They also mentioned to avoid steroids as that increases blood glucose, but I would need to research that further. Where are you doing your SRS? I think it has really helped me to avoid carbs and sugar on this journey, but it is not always easy - popcorn is my weakness - and my weight is really low. Please keep me updated on your progress. I also read the Cantin Ketogenic Diet, but the other books contradict her diet as hers is not a reduced calorie diet. It is also poorly written, I believe French is her first language.
What tests are you using to determine ketosis? The blood test strips are ridiculously expensive.

Wishing you so much success with the SRS.

__________________
Breastfeeding when diagnosed with Her2+ May 2008
Oct 2008 Double mastectomy 22/28 lymph nodes positive
Decline chemotherapy (decision I regret)
Nov 2009 Mets to lungs and bones.
Dec 2009 Start Taxotere and Herceptin, T1, T3 heal completely and lungs are clear, T2 and first rib have lytic lesions. First rib becomes sclerotic. Considered stable.
May 2011, Onc calls progression and I cross over from comparison arm of clinical trial to TDM-1
Brain scan in Sept 2011 showed small tumor in right cerebellum, did Novalis radiation.

Feb 2013 < 1cm tumor in left frontal lobe. Did Novalis in March and latest scan shows no sign of brain metastasis.
Aug 2013 did 36th round of TDM-1 Due to TDM-1 side effects, shortness of breath, and difficulty getting my balance when getting out of bed, agreed with my oncologist to stop TDM-1.
Took a six week break, bone scan showed small uptake on left first rib. CT showed hypodensities in liver (too small to biopsy) and small nodule in lungs (mediastinal).
Started Navelbine weekly. Did one round with Herceptin.
Skipped next 2 rounds, due to neutropenia. Next chemo 7th Nov - have had 3 Neupogen shots, so WBC should look better... Did not tolerate Navelbine well.
December 2013 scans show no sign of active cancer.
March 2014 - currently only on Herceptin - brain MRI clear, PET/CT two nodules in right lung show uptake
May 2014 - stop Herceptin.
Sept 22, 2014 Brain MRI clear :) PET/CT Progression in lungs.
Sept 2014, Xeloda, Tykerb and Herceptin.
Nov 2014 - Decide to take a break from all treatment.
May 2015 - Brain met radiated with Novalis
July 2015 - Have progression in right lung.
Sept 2015 - Perjeta and Herceptin alone after a 9 month break from all treatment.
Nov 2015 - Thoracentesis 1500ml removed from right lung.
Dec 2015 - Two tiny 1mm brain mets radiated in right cerebellum.
Feb 2016 - Thoracentesis 2200ml drained from right lung
Feb 2016 - Stopped Perjeta and Herceptin and started back on Kadcyla as I had no previous progression on it. After 1 cycle of Kadcyla markers begin to drop. On second cycle add Keytruda.
March 2016 - Thoracentesis 1650ml drained from right lung.
April 2016 – Thoracentesis 1500 ml drained from right lung.
June 2016 – CT scan shows progression in right lung, as well as moderate pleural effusion requiring Thoracentesis.
June 2016 – Decide to stop Keytruda, and will do chemosensitivity test through Rational Therapeutics. Plan to continue on Kadcyla for next two cycles.
July 2016 - Start weekly Abraxane with Herceptin. WBRT with hippocampal sparing, Taking Namenda. 15 sessions over 3 weeks.
Aug - Dec 2016 - 2 infusions of Navelbine, very hard on my body and still dealing with anasarca (generalized edema) 1 infusion of Havalen
My doctor wants to put me on hospice.
Dec 23rd 2016 - I am granted compassionate use of Neratanib.
May 31st 2017 - still on Neratinib, feeling good.